Thompson Lauren E, Ghimire Avisek, Wen Xia, Kim Christine, Doherty Cathleen L, Buckley Brian T, Bowles Daniel W, O'Bryant Cindy L, Jaimes Edgar A, Aleksunes Lauren M, Joy Melanie S
Department of Pharmaceutical Sciences, Skaggs School of Pharmacy and Pharmaceutical Sciences, University of Colorado Anschutz Medical Campus, Aurora, CO, USA.
Environmental and Occupational Health Sciences Institute, Rutgers University, Piscataway, NJ, USA.
J Clin Pharmacol. 2025 Jun;65(6):763-778. doi: 10.1002/jcph.6177. Epub 2024 Dec 22.
Cisplatin is a platinum-based chemotherapeutic drug used to treat many types of cancer. The aim of this study was to develop a population pharmacokinetic model that incorporates plasma unbound and bound platinum levels. Cancer patients undergoing their first or second cycle of cisplatin-containing chemotherapy (n = 33) were prospectively randomized to receive a 5-hydroxytryptamine (5-HT) antagonist (5-HTA) antiemetic (ondansetron, granisetron, or palonosetron) followed by blood collection over 10 days. Total and unbound platinum levels were quantified using inductively coupled plasma mass spectrometry. Plasma concentrations of bound and unbound platinum were used to develop a nonlinear mixed-effect pharmacokinetic model in Phoenix NLME (v8.3, Certara Inc.). A stepwise search was used to screen covariates that influenced pharmacokinetic parameters. A compartment for bound platinum was added to a two-compartment unbound platinum model to create a combined platinum model. The volume of the central compartment for unbound platinum (V1_u) was significantly impacted by previous cisplatin exposure and the intercompartmental clearance of unbound platinum (CL2_u) was significantly influenced by concomitant lorazepam use. The models also suggested ondansetron- and granisetron-treated subjects had a 331% and 114% increase, respectively, in circulating exposures to unbound platinum than palonosetron-treated subjects. The results suggest platinum pharmacokinetics are altered by concomitant 5-HTA antiemetic use, concomitant lorazepam use, and previous exposure to cisplatin. Ondansetron and granisetron co-treatment increased unbound platinum exposure compared to palonosetron co-treatment, suggesting that palonosetron may be a preferred 5-HTA to reduce the risk of cisplatin-induced kidney injury.
顺铂是一种基于铂的化疗药物，用于治疗多种类型的癌症。本研究的目的是建立一个纳入血浆中游离铂和结合铂水平的群体药代动力学模型。接受含顺铂化疗第一或第二周期的癌症患者（n = 33）被前瞻性随机分组，接受5-羟色胺（5-HT）拮抗剂（5-HTA）止吐药（昂丹司琼、格拉司琼或帕洛诺司琼）治疗，随后在10天内采集血液样本。使用电感耦合等离子体质谱法定量总铂和游离铂水平。结合铂和游离铂的血浆浓度用于在Phoenix NLME（v8.3，Certara公司）中建立非线性混合效应药代动力学模型。采用逐步搜索法筛选影响药代动力学参数的协变量。在一个二室游离铂模型中添加一个结合铂室，以创建一个联合铂模型。游离铂中央室的容积（V1_u）受既往顺铂暴露的显著影响，游离铂的室间清除率（CL2_u）受同时使用劳拉西泮的显著影响。模型还表明，与接受帕洛诺司琼治疗的受试者相比，接受昂丹司琼和格拉司琼治疗的受试者循环中游离铂的暴露量分别增加了331%和114%。结果表明，铂的药代动力学受同时使用5-HTA止吐药以及同时使用劳拉西泮和既往顺铂暴露的影响。与帕洛诺司琼联合治疗相比，昂丹司琼和格拉司琼联合治疗增加了游离铂的暴露量，这表明帕洛诺司琼可能是降低顺铂诱导的肾损伤风险的首选5-HTA。
